Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism.
We have successfully delivered a reactive alkylating agent, chlorambucil (Cbl), to the mitochondria of mammalian cells. Here, we characterize the mechanism of cell death for mitochondria-targeted chlorambucil (mt-Cbl) in vitro and assess its efficacy in a xenograft mouse model of leukemia. Using a ρ...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0060253&type=printable |
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| _version_ | 1850138184465252352 |
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| author | Rida Mourtada Sonali B Fonseca Simon P Wisnovsky Mark P Pereira Xiaoming Wang Rose Hurren Jeremy Parfitt Lesley Larsen Robin A J Smith Michael P Murphy Aaron D Schimmer Shana O Kelley |
| author_facet | Rida Mourtada Sonali B Fonseca Simon P Wisnovsky Mark P Pereira Xiaoming Wang Rose Hurren Jeremy Parfitt Lesley Larsen Robin A J Smith Michael P Murphy Aaron D Schimmer Shana O Kelley |
| author_sort | Rida Mourtada |
| collection | DOAJ |
| description | We have successfully delivered a reactive alkylating agent, chlorambucil (Cbl), to the mitochondria of mammalian cells. Here, we characterize the mechanism of cell death for mitochondria-targeted chlorambucil (mt-Cbl) in vitro and assess its efficacy in a xenograft mouse model of leukemia. Using a ρ° cell model, we show that mt-Cbl toxicity is not dependent on mitochondrial DNA damage. We also illustrate that re-targeting Cbl to mitochondria results in a shift in the cell death mechanism from apoptosis to necrosis, and that this behavior is a general feature of mitochondria-targeted Cbl. Despite the change in cell death mechanisms, we show that mt-Cbl is still effective in vivo and has an improved pharmacokinetic profile compared to the parent drug. These findings illustrate that mitochondrial rerouting changes the site of action of Cbl and also alters the cell death mechanism drastically without compromising in vivo efficacy. Thus, mitochondrial delivery allows the exploitation of Cbl as a promiscuous mitochondrial protein inhibitor with promising therapeutic potential. |
| format | Article |
| id | doaj-art-e03cf7fdc1eb452ebcf2372fb72dfd81 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-e03cf7fdc1eb452ebcf2372fb72dfd812025-08-20T02:30:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0184e6025310.1371/journal.pone.0060253Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism.Rida MourtadaSonali B FonsecaSimon P WisnovskyMark P PereiraXiaoming WangRose HurrenJeremy ParfittLesley LarsenRobin A J SmithMichael P MurphyAaron D SchimmerShana O KelleyWe have successfully delivered a reactive alkylating agent, chlorambucil (Cbl), to the mitochondria of mammalian cells. Here, we characterize the mechanism of cell death for mitochondria-targeted chlorambucil (mt-Cbl) in vitro and assess its efficacy in a xenograft mouse model of leukemia. Using a ρ° cell model, we show that mt-Cbl toxicity is not dependent on mitochondrial DNA damage. We also illustrate that re-targeting Cbl to mitochondria results in a shift in the cell death mechanism from apoptosis to necrosis, and that this behavior is a general feature of mitochondria-targeted Cbl. Despite the change in cell death mechanisms, we show that mt-Cbl is still effective in vivo and has an improved pharmacokinetic profile compared to the parent drug. These findings illustrate that mitochondrial rerouting changes the site of action of Cbl and also alters the cell death mechanism drastically without compromising in vivo efficacy. Thus, mitochondrial delivery allows the exploitation of Cbl as a promiscuous mitochondrial protein inhibitor with promising therapeutic potential.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0060253&type=printable |
| spellingShingle | Rida Mourtada Sonali B Fonseca Simon P Wisnovsky Mark P Pereira Xiaoming Wang Rose Hurren Jeremy Parfitt Lesley Larsen Robin A J Smith Michael P Murphy Aaron D Schimmer Shana O Kelley Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism. PLoS ONE |
| title | Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism. |
| title_full | Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism. |
| title_fullStr | Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism. |
| title_full_unstemmed | Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism. |
| title_short | Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism. |
| title_sort | re directing an alkylating agent to mitochondria alters drug target and cell death mechanism |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0060253&type=printable |
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